Cervical, anal, and oral dysplasias are precursors of epithelial cancers caused by persistent human papillomavirus. These pre-malignant lesions are especially common with immunosuppression as occurs with AIDS and post-transplantation. Anal dysplasia has emerged with increasing frequency in the HIV infected population. Current medical treatments for HPV are not highly effective and no treatment is specifically antiviral. Without an effective inhibitor, millions of women and men will develop serious and life- threatening disease. We are uniquely positioned to identify an inhibitor of papillomavirus because of our combined experience and expertise in the molecular biology of papillomavirus, structural biology, and synthetic chemistry. HPV proteins represent specific targets for therapeutic intervention. The viral E6 protein represents an attractive target for therapeutic intervention because of its multiple and essential roles in viral propagation and cellular transformation. E6-binding proteins possess a conserved amino acid sequence arranged in a helical structure. The goal of this project is to obtain small molecules that mimic the helix and thus interfere with the interactions that E6 makes with cellular proteins. In Aim 1, we will improve the efficacy of a lead small molecule inhibitor of HPV-16 E6 functions. New compounds will be based on exploring chemical space around the two lead chemical platforms and optimizing compounds for matches with the E6-binding pharmacophore. The second Aim examines the biological and biochemical consequences of E6 inhibition by high affinity compounds that inhibit E6 interactions with its cellular targets. PUBLIC HEALTH RELEVANCE Papillomaviruses cause benign infections that can become malignant. We describe experiments designed to build on our progress to identify and characterize drug-like compounds that inhibit the functions of the viral E6 protein. E6 is necessary for viral replication and for oncogenic progression. These compounds can be advanced to treat cervical, anogenital and head and neck cancers and their precursor lesions.